This proposal will demonstrate the feasibility of creating and formulating a dietary supplement of creatine with improved oral absorption characteristics. Such an improvement would allow increased use of creatine supplement to augment and complement existing treatments for conditions where muscle fatigue and weakness are a problem. It is known that increasing dietary intake of creatine can improve muscle function by increasing creatine phosphate levels in the cell. However, due to limited oral absorption, current embodiments of creatine dietary supplements require the administration of large doses that often result in undesired side-effects such as bloating, cramping and diarrhea. It is hypothesized that by chemically modifying creatinine to form creatine esters (CE), novel supplements with improved oral absorption and muscle performance and muscle performance can be obtained. The specific aims of this proposal are to synthesize a series of CE compounds and through in vitro screening assays and in vivo pharmacokinetic studies, determine which one(s) have improved oral absorption compared to creatine monohydrate, the current preferred form of dietary supplement. Finally, suitable liquid and solid dietary supplement formulations will be identified for the lead CE compound. This Phase I proposal will provide proof-of-concept supplements have improved oral absorption over products current available. PROPOSED COMMERCIAL APPLICATIONS: Creatine dietary supplements represent an estimated $200-300 million in annual sales. The technology described in this proposal will result in a chemically-modified form of creatine with improved oral absorption and more convenient dosage formulations compared to currently available creatine nutritional supplements. Such improvements would result in a substantially superior product with applications in the treatment of disease states and conditions involving reduced muscle function.